PROJECT SUMMARY The average age of the U.S. population continues to increase, causing a surge in the size of the geriatric population. While only 13% of the US population is 65 and older, they consume over 36% of personal health expenditures. Cardiovascular disease (CVD) is a major contributor to both the mortality and health care costs among the elderly population. It is becoming evident that aging results in well-defined structural and functional changes in the blood vessel wall that renders the cardiovascular system prone to disease even in the absence of traditional risk factors. Moreover, age-related alterations render the aged vasculature more susceptible to the damaging effects of the common CV risk factors. Intrinsic cardiac aging in the murine model closely recapitulates age-related cardiac changes in humans (left ventricular hypertrophy, fibrosis and diastolic dysfunction), while the phenotype of vascular aging includes endothelial dysfunction, reduced vascular elasticity, and chronic vascular inflammation. Recent findings suggest that age-related diseases could be delayed by modulating senescence. Based on work from this laboratory and others, PAI-1 is now recognized as a fundamental driver of tissue senescence. The parent R01 of this revision supports an investigative program directed to define the role of PAI-1 in the molecular pathogenesis of senescence and aging-related changes in the cardiovascular system using murine models of accelerated aging. However, while mice with accelerated aging phenotype due to various mutations provide a fast and cost-effective model to study the role of PAI-1 in aging, there is a possibility that their phenotypes might not be relevant to aging in non-mutant animals. Accordingly, we propose to test the hypothesis that PAI-1 plays a fundamental role in the development of vascular senescence and aging not only in mice with an accelerated aging phenotype, but also in naturally aged mice. The specific aims of this proposal are designed to investigate whether pharmacologic modulation of PAI-1 activity protects against the development of vascular abnormalities in aging animals with increased cardiovascular risk due to obesity and elevated blood pressure. We anticipate that the studies proposed here will provide proof of principle that pharmacological inhibition of PAI-1 activity is a rational therapeutic approach in preventing the cardiovascular manifestations of aging.